Is KRT4 p.Val103Ile (c.307G>A) pathogenic?

KRT4 p.Val103Ile (c.307G>A) is classified Uncertain significance in KRT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-27). AlphaMissense: likely benign (0.0917); Very rare (popmax 0.00917%, afr); Associated with Inborn genetic diseases.

What condition is associated with KRT4 p.Val103Ile (c.307G>A)?

KRT4 p.Val103Ile (c.307G>A) is associated with Inborn genetic diseases (ClinVar).

How common is KRT4 p.Val103Ile (c.307G>A) in the general population?

KRT4 p.Val103Ile (c.307G>A) is very rare (popmax 0.00917%, afr) (gnomAD).

What do computational predictors say about KRT4 p.Val103Ile (c.307G>A)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

KRT4 p.Val103Ile

c.307G>A · rs371081693 · VCV2217368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00917%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.32, phastCons 0.87
Regional constraint	o/e 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	17.44	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00917% African / African-American · 2/21,806 alleles

Filtering AF 0.00632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00574%

Overall 0.00701% 71/1,013,500 alleles · very rare exomes 63/1,005,234 · genomes 8/8,266 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00917%	10,903
European (non-Finnish)	0.00791%	12,641
Remaining individualsnot grpmax-eligible	0.0029%	34,530
South Asian	0.00235%	42,536

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: KRT4
Protein: p.Val103Ile
Coding: c.307G>A
MANE Select: NM_002272
dbSNP: rs371081693
Type: single nucleotide variant
Location: chr12:52813752 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 103: the 'head' region

Full KRT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRT4 p.Ala106Gly Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp153Asn Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp247Glu Uncertain significance ★★ same condition
KRT4 p.His398Tyr Likely benign ★★ same condition
KRT4 p.Ala106Thr Uncertain significance ★ ⚠ same condition
KRT4 p.Ala20Asp Uncertain significance ★ ⚠ same condition
KRT4 p.Ala278Glu Uncertain significance ★ ⚠ same condition
KRT4 p.Ala278Val Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/krt4-p-val103ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown